Seeing Heart Disease More Clearly

Using cutting-edge molecular imaging to peer into a patients blood vessels, a small biotechnology company hopes to spot heart attacks before they happen. St. Louis-based Kereos is working with pharmaceutical giant Bristol-Myers Squibb to develop contrast agents that will help identify the plaque inside arteries that can lead to heart attacks. Bristol-Myers is working to test and commercialize a molecular imaging agent created by Kereos to make such plaque show up in a magnetic resonance imaging (MRI) scan. There currently isnt any diagnostic or any imaging agent that is able to find and diagnose unstable plaque, says Kereos president and CEO Robert Beardsley.

Beardsley says researchers think that unstable plaqueso-called because bits of it break off, leaving tears that may lead to blood clotsis responsible for 50 to 85 percent of fatal heart attacks. While conventional imaging techniques can see if a buildup of plaque has narrowed the arteries leading to the heart, they can’t tell much about the quality of the plaque.

Molecular imaging, the ability to watch the action of specific molecules within a human body, is widely seen as the next revolution in medical diagnosis. Researchers believe the various techniques lumped under the heading of molecular imaging will allow doctors to detect not only the effects of diseases but also disease processes. Molecular imagingtargeted imaging, if you willgives us the ability to find and light up tissue that says I’m not just a lump, I’m this kind of disease.’ And that’s huge, says Beardsley.

Kereos, founded in 1999, has come up with an imaging agent that will selectively stick to the damaged plaque and shine brightly in an MRI scan. It consists of a droplet, about 250 nanometers in diameter, of perfluorocarbon, an inert liquid, surrounded by a layer of lipid, or fat. The lipid is hydrophobic, so the water in blood plasma repels it and causes it to stick to the perfluorocarbon. The lipid in turn holds a layer of chelated gadolinium, a metal chemically bonded to organic molecules to render it nontoxic. The gadolinium, long used in blood contrast agents, will stand out strongly in an MRI image. Finally, scattered across the surface of the droplet are a series of targeting ligands – molecules that anchor one end of themselves in the lipid while their other end will stick to fibrin, a covering that forms over the surface of tears in the plaque.

Other makers of contrast agents have used ligands for such purposes, binding one end to a single gadolinium molecule and the other to the target. But because the components in Kereos’s particle are not chemically bondedthey’d just rather stick together than to anything else in their environmentone droplet holding only 100 ligands can carry 100,000 gadolinium molecules, increasing by 1,000-fold the brightness at each binding site. That’s why we can do what other people can’t with an MRI, Beardsley says.

With this new tool, he says, doctors will be able to get a better idea of what’s going on in a patient’s arteries. That could lead to a better understanding of the role of unstable plaque in heart attacks, and let doctors tailor treatment to an individual patient.

Earlier this month, Kereos received a $7.3 million grant from the National Heart, Lung, and Blood Institute to further develop its contrast agent and to work on a drug to treat unstable plaque. The grant will fund research performed jointly by Kereos and by the company’s scientific cofounder, Samuel Wickline, a professor of medicine and of biomedical engineering at the Washington University School of Medicine in St. Louis .

Beardsley hopes that the drug researchers are working on will be ready for clinical trials in 2007. If such a drug is developed, the same molecule that delivers the contrast agent might also carry the medication to where it’s needed. That targeting strategy might work with cancer, too. Kereos and Bristol-Myers Squibb are developing a contrast agent, similar to that for plaque, that they hope will bind to tumors too small to see with current imaging techniques. One formulation of the agent would locate very early stage tumors; a different version would carry a drug to kill the cancer cells.

Other types of imaging are also under development, including radionucleotide imaging, in which a radioactive substance is linked to something that will bind to a disease site. Beardsley says the Kereos contrast agent should be safer than radionucleotide agents, which also show up brightly on a scan but leave hospitals to deal with radioactive waste. The Kereos product will have very low toxicity, he says, because the perfluorocarbon is eventually carried to the lungs and exhaled, the lipids are absorbed by the body, and the targeting ligands are processed by the kidneys. Bristol-Myers Squibb expects to begin animal studies to test the safety of the plaque contrast agent sometime next year.

The National Institute of Biomedical Imaging and Bioengineering is supporting a variety of research into molecular imaging, with roughly $15 million in grants in 2003. Alan McLaughlin, a program director at the institute, expects that in about 10 years there will be enough technology available to start providing individualized treatment to patients. It’s important in studying health problems and disease to know what’s going wrong inside a cell, McLaughlin says. Molecular imaging provides specific, potentially quantifiable markers to study disease processes. And he thinks Kereos’s contrast agent is a feasible approach to tackling heart disease. There are all sorts of ways for treating plaque, he says, but you’ve got to know it’s there before you can treat it.